Abstract

1436

Introduction: Conventional treatment of human head and neck squamous cell carcinoma (HNSCC) involves the use of a platinum agent or a taxane in combination with radiation therapy (RT). However, the addition or substitution of anti-EGFR therapy for chemotherapy may enhance efficacy and decrease the incidence of toxicities associated with chemotherapy and RT in combination. The effectiveness of anti-EGFR therapy in patients with HNSCC is variable and appears to depend on the relative EGFR-dependence and EGFR expression of tumors in this patient population. Vandetanib (VAN) is an orally available and potent inhibitor of VEGFR2 and EGFR tyrosine kinases. The dual inhibitory activity of VAN suggests that it may have therapeutic utility in tumors that are either sensitive or resistant to EGFR signaling inhibitors. The aim of this study was to investigate the activity of VAN in combination with docetaxel (DTX) and/or RT in UMSCC10 HNSCC tumor xenografts, which do not express EGFR and are resistant to the EGFR signaling inhibitors gefitinib and cetuximab. Methods: UMSCC10 tumor xenografts were established in nude mice (n= 5-10 per group) with an average volume at the start of treatment of 284 ± 172 mm3. Mice received VAN (15 mg/kg/day p.o.), DTX (9 mg/kg every 10 days [DTX9] or 3 mg/kg 2x weekly [DTX3] i.v.) and/or RT (4 Gy 2x weekly for 2 weeks) alone and in combinations. The DTX dosing regimens were chosen to approximate human dosing at 100 mg/m2 q21d (DTX9) and 30 mg/m2 weekly (DTX3) based on comparative pharmacokinetics. Results: VAN alone had no effect on tumor growth but was comparable to DTX3 in enhancing RT response showing an ~80% decrease in growth rate following RT therapy and 33-43% of animals maintaining tumor regression. DTX9 was superior to the more protracted scheduling (DTX3), with 33% of the DTX9 animals across groups showing complete responses (no palpable tumor) compared to only 24% of the DTX3 animals. Combining VAN with DTX9 was superior to DTX9 alone with a 15% increase in response rates with the addition of VAN. The DTX9 and RT combination group showed the most durable response, with inhibition of tumor growth maintained after the 28-day treatment period and 64% of the animals showing a complete response. The triple combination groups (VAN/DTX/RT) showed similar responses to DTX/RT groups. Conclusions: The results of this study show that the growth of EGFR-null UMSCC10 HNSCC xenografts was not significantly inhibited by VAN (15 mg/kg/day) alone but that the addition of VAN enhances the response to both DTX and RT. Further studies are ongoing in HNSCC tumors to determine if changes to the scheduling of RT or DTX can further enhance the effectiveness of combination treatment with VAN. The relative contribution of anti-VEGFR and anti-EGFR activity to the antitumor effects of VAN in this tumor type is also being explored.